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Commentary (Fowble): Treatment of Complications After Breast-Conservation Therapy

Commentary (Fowble): Treatment of Complications After Breast-Conservation Therapy

The adverse effects of cancer treatment can be divided into three groups: those that are significant and life-threatening, those that are not life-threatening but result in lifestyle changes, and those that are of minor severity and limited duration. The potential significant and lifethreatening effects of radiation in the treatment of breast cancer include cardiac toxicity and carcinogenesis. Two prospective randomized trials of breast-conserving surgery and radiation have demonstrated no increase in the risk of non-breast cancer death at 20 and 25 years among patients who received radiation compared to those treated by mastectomy.[1,2]

Frassica et al have focused their discussion on the non-life-threatening effects of conservative surgery and radiation for early-stage invasive breast cancer. However, it is important to recognize that the morbidity often attributed to a single intervention can be influenced by patientrelated factors as well as the use of other treatment modalities. In breastconservation therapy, the goal is to optimally integrate surgery, radiation, and systemic therapy to minimize the risk of recurrence and complications and maximize cosmesis.

Patient-Related Factors

The incidence of lymphedema and arm morbidity has been associated with patient age, although the findings have been somewhat inconsistent. Powell et al[3] reported an increased incidence of lymphedema among older women who underwent conservative surgery and radiation. Mendelblatt et al[4] reported more than a doubling of the prevalence of arm problems in women at least 67 years of age with a history of preexisting arthritis who underwent axillary dissection. In contrast, Yap et al[5] noted a higher incidence of shoulder and arm symptoms among women aged 50 to 59 years who had undergone axillary dissection compared to women aged 60 years and older.

Obesity is significantly associated with an increased risk of lymphedema in women treated with conservative surgery, axillary dissection, and radiation.[6] In addition, large breast size has been associated with diminished cosmesis.

Smoking has an impact on wound healing and infection, but has not been associated with an increased risk of arm symptoms in women undergoing breast-conservation therapy.[5]

Patients with a preexisting history of collagen vascular disease (especially scleroderma) have been reported to experience soft-tissue and bone necrosis with conventional doses of radiation.[7,8] Radiation is generally contraindicated in these patients.

In a recent series,[9] investigators reported a significant incidence of soft-tissue fibrosis and necrosis in women with breast cancer and ataxia telangiectasia mutated (ATM) gene heterozygosity treated with radiation. Some evidence indicates that ATM heterozygosity may be more common among breast cancer patients than the 1% incidence in the general population.[10]

Treatment-Related Factors

Surgical resection of the primary tumor must achieve a balance between the volume of breast tissue excised to achieve negative margins and that required to maintain acceptable cosmesis. Large surgical resections increase the risk of infection and seroma formation and diminish the cosmetic result. Infection and seroma formation contribute to the risk of lymphedema and breast edema. Axillary dissection is the primary factor contributing to the risk of lymphedema in the absence of axillary radiation.[4,5,11] In addition, axillary dissection increases the incidence of breast edema with radiation.

Radiation technique can also have an impact on the incidence of complications. The use of large daily fractions (> 2 Gy) has resulted in significant late (30 years) sequelae (fibrosis, edema, and neuropathy) in one series.[12] Excessive doses to normal tissue from overlapping fields or suboptimal treatment planning with significant dose inhomogeneity will result in an increased incidence of fibrosis and rib fractures and diminished cosmesis. The regions treated with radiation (breast vs breast and regional nodes) will influence the observed morbidity. The use of radiation to the axilla following an axillary dissection significantly increases the risk of lymphedema.[3,11,13] The use of brachytherapy either as a boost treatment or alone has been associated with an increased incidence of fat necrosis.

Systemic Therapy

The use of chemotherapy in conjunction with conservative surgery and radiation has been reported to diminish cosmetic results at 3 years but not at 5 years.[13] Patients who receive the CMF regimen (cyclophosphomide [Cytoxan, Neosar], methotrexate, fluorouracil) either concurrently or sequentially have had an increased incidence of moist desquamation (acute skin reaction) and myositis.[ 13,14] In one series, chemotherapy was associated with an increased incidence of lymphedema.[13] However, this finding was not observed in the series reported by Powell et al.[3] Chemotherapy has not been associated with an increased risk of rib fractures. There is little information regarding the impact of doxorubicinbased regimens or taxanes on cosmesis or complications in patients treated with conservative surgery and radiation.

Tamoxifen has been reported to increase the risk of breast edema in patients receiving radiation.[15] This observation has led some physicians to advise against the concurrent use of radiation and tamoxifen for earlystage invasive breast cancer. Tamoxifen has not been reported to adversely affect cosmesis or the incidence of rib fractures.

Minimizing Morbidity

Overall, the incidence of complications following conservative surgery and radiation for early-stage invasive cancer is quite low. Less than 1% to 2% of patients experience fat necrosis or soft-tissue or bone necrosis, and good to excellent cosmesis is achieved in 85% to 90%.[16,17] Lymphedema has been reported in 5% to 10% of patients who underwent axillary dissection at 10 years.[3,13,16] Although it is difficult to modify the patient-related factors of collagen vascular disease and ATM heterozygosity, recognition of their effect on radiation-related morbidity should influence treatment recommendations.

Weight loss in obese women and cessation of smoking can potentially diminish side effects. The avoidance of unnecessary large surgical resections will decrease the risk of infection, seroma, breast edema, lymphedema, and poor cosmesis, and the increasing use of sentinel lymphadenectomy will decrease arm morbidity.[18] Improved delivery of radiation to the breast with dose optimization by threedimensional treatment planning, with or without intensity-modulated radiation, will help to minimize toxicity to normal tissue.[19]

The integration of conservative surgery and radiation with doxorubicin-based chemotherapy regimens or taxanes requires further evaluation. Avoiding the use of concurrent tamoxifen and radiation especially in large-breasted women will decrease breast edema. Surgery, radiation, and chemotherapy protocols for early-stage invasive breast cancer continue to evolve, with the emphasis on minimizing both recurrence and morbidity.

Ipsilateral Breast Tumor Recurrence

Frassica et al focus their discussion of the management of an ipsilateral breast tumor recurrence after breast-conserving surgery and radiation on further attempts to preserve the affected breast and, in particular, on the results of reirradiation. Given their discussion of the adverse effects of excessive doses of radiation on normal tissues (bone and soft-tissue fibrosis and necrosis), one might question the wisdom of considering such an approach. In addition, there is the added concern of a radiation-induced malignancy, especially a sarcoma.

Potential candidates for treatment directed to less than the entire breast after conservative surgery and radiation would be those whose recurrence is likely to be removed entirely by a limited surgical resection. That is, the ideal candidate would be an older woman with very small invasive ductal cancer (without an extensive intraductal component or lymphatic invasion) that is estrogen-receptor-positive and that appeared more than 5 years after initial treatment for node-negative disease.

The role of a second course of localized radiation as opposed to wide excision alone is unknown. Certainly, the former treatment has the potential for greater harm than the latter. Even with the most favorable initial tumors (≤ 1 cm, node-negative), treatment to the entire breast with radiation diminished the rate of ipsilateral breast tumor recurrences in the National Surgical Adjuvant Breast and Bowel Project B-21 trial.[20] Therefore, mastectomy should remain the recommended surgical treatment for an isolated local reccurence after conservative surgery and radiation.

Financial Disclosure: The author has no significant financial interest or other relationship with the manufacturers of any products or providers of any service mentioned in this article.

References

1. Veronesi U, Cascinelli N, Mariani L, et al: Twenty-year follow-up of a randomized study comparing breast-conserving surgery with radical mastectomy for early breast cancer. N Engl J Med 347:1227-1234, 2002.
2. Fisher B, Jeong J, Anderson S, et al: Twenty-five year follow-up of a randomized trial comparing radical mastectomy, total mastectomy, and total mastectomy followed by radiation. N Engl J Med 347:567-565, 2002.
3. Powell SN, Taghian AG, Kachnic LA, et al: Risk of lymphedema after regional node irradiation with breast conservation therapy. Int J Radiat Oncol Biol Phys 55:1209-1215, 2003.
4. Mendelblatt JS, Edge SB, Meropol NJ, et al: Sequelae of axillary lymph node dissection in older women with stage I and II breast carcinoma. Cancer 95:2445-2454, 2002.
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10. Swift M, Morell D, Massey RB, et al: Incidence of cancer in 161 families affected by ataxia telangiectasia. N Engl J Med 325:1831-1836, 1991.
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12. Johansson S, Svensson H, Denekamp J: Dose response and latency for radiationinduced fibrosis, edema, and neuropathy in breast cancer patients. Int J Radiat Oncol Biol Phys 52:1207-1219, 2002.
13. Markiewicz DA, Schultz DJ, Haas JA, et al: The effects of the sequence and type of chemotherapy and radiation therapy on cosmesis and complications after breast conservation therapy. Int J Radiat Oncol Biol Phys 35:661-668, 1996.
14. Dubey A, Recht A, Come SE, et al: Concurrent CMF and radiation therapy for early stage breast cancer: Results of a pilot study. Int J Radiat Oncol Biol Phys 45:877-884, 1999.
15. Fowble B, Fein DA, Hanlon AL, et al: The impact of tamoxifen on breast recurrence, cosmesis, complications and survival in estrogen receptor-positive early-stage breast cancer. Int J Radiat Oncol Biol Phys 35:669-677, 1996.
16. Fowble BL, Solin LJ, Schultz DJ, et al: Ten-year results of conservative surgery and radiation for stage I-II breast cancer. Int J Radiat Oncol Biol Phys 21:269-277, 1991.
17. Pierce SM, Recht A, Lingos T, et al: Long-term radiation complications following conservative surgery (CS) and radiation therapy (RT) in patients with early stage breast cancer. Int J Radiat Oncol Biol Phys 23:915- 923, 1992.
18. Sener SF, Winchester DJ, Martz LH, et al: Lymphedema after sentinel lymphadenectomy for breast carcinoma. Cancer 92:748- 752, 2001.
19. Vicini FA, Sharpe M, Kestin L, et al: Optimizing breast cancer treatment with intensity- modulated radiotherapy. Int J Radiat Oncol Biol Phys 54:1336-1344, 2002.
20. Fisher B, Bryant J, Dignam JJ, et al: Tamoxifen, radiation therapy or both for prevention of ipsilateral breast tumor recurrence after lumpectomy in women with invasive breast cancers of one centimeter or less. J Clin Oncol 20:4141-4149, 2002.
 
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